Roles of LIM cofactors for regulating ERalpha during oncogenesis and development

LIM 辅助因子在肿瘤发生和发展过程中调节 ERα 的作用

• 批准号: 7777401
• 负责人: INGOLF M BACH
• 金额: $ 33.72万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777401
• 关键词: Address; Affect; Binding Proteins; Biochemical Genetics; Biological; Biological Assay; Breast Cancer Cell; Cancer Patient; Cancer Prognosis; Cell Culture Techniques; Complex; Data; Development; Dominant-Negative Mutation; Drug Design; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Fingers; Gene Activation; Gene Targeting; Genes; Genetic Transcription; Human; Human Development; Knock-out; Knowledge; LIM Domain; Lead; MCF7 cell; Malignant Neoplasms; Mammary gland; Maps; Mediating; Medical; Molecular; Mus; Nuclear; Oncogenic; Pathway interactions; Patients; Positioning Attribute; Proteins; Puberty; Publishing; Recruitment Activity; Regulation; Reporting; Research; Role; Signal Pathway; Tertiary Protein Structure; Testing; Tissue Microarray; Transcriptional Activation; Transcriptional Regulation; Ubiquitin; United States; Woman; Work; cancer type; chromatin immunoprecipitation; cofactor; homeodomain; human RBX1 protein; in vivo; malignant breast neoplasm; mammary gland development; men; mouse model; multicatalytic endopeptidase complex; novel strategies; overexpression; promoter; protein complex; public health relevance; research study; therapy development; transcription factor; tumor; tumorigenesis; ubiquitin ligase

DESCRIPTION (provided by applicant): The number of new cases of breast cancer has increased by about one percent per year in the United States since the 1940s. For 2007, an estimated 212,000 new cases of invasive breast cancer are expected to occur among women and men in the United States alone. Although breast cancer is currently subject of intense research an estimated 45,000 patients in the United States will still die from this type of tumour in 2007, demonstrating how little is known about the development and treatment of this particular type of cancer. Estrogen stimulates the proliferation of the most common type of human breast cancer that expresses estrogen receptor ? (ER?) via transcriptional gene activation, placing ER? in a key position for the development of breast cancer. Although a significant body of research on ER? has been carried out over the years, the knowledge of its transcriptional mechanisms remains limited. In our preliminary experiments we have discovered a new set of cofactors for ER?, consisting of the nuclear LIM cofactors RING finger LIM domain-binding protein (RLIM) and cofactor of LIM homeodomain transcription factors (CLIM), that associate with and are able to modulate the transcriptional activity of ER? in breast cancer cells. Furthermore, our results show a highly significant correlation of high CLIM expression with ER/PR positive breast cancers in human patients. We hypothesize that LIM cofactors RLIM and CLIM decisively regulate the biological activity of ER?. This proposal sets out to establish the roles of LIM cofactors 1) for the regulation of ER? -mediated transcriptional activity, 2) the regulation of known cofactor complexes recruited by ER? and 3) the significance for human breast cancer as well as for mammary gland development following puberty in mice. Thus, the proposed research will greatly add to the knowledge of ER? regulation with strong implications for the development of breast cancer thereby likely unraveling new strategies for the design of drugs to treat breast cancer patients. PUBLIC HEALTH RELEVANCE: Estrogen receptor ? (ER?) is decisively involved in the development of many human breast cancers. The proposed experiments in this application will identify a set of cofactors for ER? that critically regulates its transcriptional and biological activity, thereby unravelling new mechanisms of ER? regulation. The expected results will lead to novel strategies for the design of drugs against breast cancer.

描述（由申请人提供）：自1940年代以来，美国每年的新乳腺癌病例数量增加了约百分之一。 2007年，仅在美国，预计将发生212,000例新的侵入性乳腺癌病例。尽管目前乳腺癌目前受到严格的研究，但在2007年，美国仍将死于这种类型的肿瘤，这表明对这种特殊类型的癌症的发展和治疗知之甚少。雌激素刺激表达雌激素受体的最常见类型的人类乳腺癌的增殖？ （er？）通过转录基因激活，放置ER？在乳腺癌发展的关键位置。虽然对ER的大量研究？多年来一直进行的，其转录机制的知识仍然有限。在我们的初步实验中，我们发现了一组新的ER的辅助因子，由核lim辅助因子环形指能LIM结构域结合蛋白（RLIM）和LIM同源域转录因子（攀登）的辅因子组成，它们与ER的转录活性相关联并能够调节ER的转录活性？在乳腺癌细胞中。此外，我们的结果表明，在人类患者中，高攀爬表达与ER/PR阳性乳腺癌的高度显着相关。我们假设Lim辅助因子Rlim并决定降低ER的生物学活性。该提议旨在确定LIM辅助因子的作用1）对ER的调节？ - 介导的转录活性，2）ER募集的已知辅因子复合物的调节？ 3）小鼠青春期后对人类乳腺癌以及乳腺发育的重要性。因此，拟议的研究大大增加了ER的知识吗？调节对乳腺癌的发展具有很强的影响，从而可能揭示了设计药物治疗乳腺癌患者的新策略。公共卫生相关性：雌激素受体？ （er？）果断地参与了许多人类乳腺癌的发展。本应用程序中提出的实验将确定一组ER的辅助因子？严格地调节其转录和生物学活性，从而揭示ER的新机制？规定。预期的结果将导致针对乳腺癌的药物设计的新策略。